Only one out of three patients with insulin-dependent diabetes is at risk of ever developing renal complications. Recently we obtained preliminary data which suggest that the risk of this complication might be genetically determined. To study further the genetic determinants of diabetic nephropathy, the affected sib-pair method will be used. From among the diabetic patients of the Joslin Clinic, pairs of siblings will be identified in which both have nephropathy. DNA will be isolated from blood obtained from the patients and their parents. Using currently available cDNA probes that identify four polymorphic cleavage sites on the tip of the long arm of chromosome 13, the distribution of the number of haplotypes shared by affected sib-pairs will be determined. If the proportion of affected sib-pairs which share two haplotypes identical by descent is larger than the expected 25%, this will be proof that one or more defects in the regulatory or structural part of a gene on the tip of chromosome 13 (most likely a gene for the alpha1 or alpha2 chain of type IV collagen) contributes to the development of diabetic nephropathy. Simultaneous with the evaluation of the contribution of type IV collagen genes to the risk of diabetic nephropathy, the role of genetic predisposition to hypertension will be examined as well. The two factors might operate separately or interdependently. Should our preliminary findings be confirmed in this study, totally new approaches could be taken in research on the determinants of diabetic nephropathy and in the care for diabetic patients. Only susceptible individuals would be targeted for special preventive programs, while those without this susceptibility could be spared unnecessary effort and any side effects that would accompany these programs.